Pyrazole compositions useful as inhibitors of ERK

ABSTRACT

Described herein are compounds that are useful as protein kinase inhibitors having the formula:  
                 
 
     where R 1-4 , Q, and T are described in the specification. The compounds are useful for treating disease states in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.

[0001] This application claims the priority to co-pending InternationalPatent Application PCT/US03911, filed Feb. 5, 2001, which claimspriority of U.S. Provisional Application serial No. 60/180,506 filedFeb. 5, 2000; U.S. Provisional Application serial No. 60/242,935 filedOct. 24, 2000; and U.S. Provisional Application serial No. 60/191,956filed Mar. 24, 2000. The entirety of which is herein incorporated byreference.

FIELD OF THE INVENTION

[0002] The present invention is in the field of medicinal chemistry andrelates to pyrazole compounds that are protein kinase inhibitors,especially inhibitors of ERK, compositions containing such compounds andmethods of use. The compounds are useful for treating cancer and otherdisease states that are alleviated by protein kinase inhibitors.

BACKGROUND OF THE INVENTION

[0003] Mammalian mitogen-activated protein (MAP)1 kinases areserine/threonine kinases that mediate intracellular signal transductionpathways (Cobb and Goldsmith, 1995, J. Biol. Chem., 270, 14843; Davis,1995, Mol. Reprod. Dev. 42, 459). Members of the MAP kinase family sharesequence similarity and conserved structural domains, and include theERK (extracellular signal regulated kinase), JNK (Jun N-terminalkinase), and p38 kinases. JNKs and p38 kinases are activated in responseto the pro-inflammatory cytokines TNF-alpha and interleukin-1, and bycellular stress such as heat shock, hyperosmolarity, ultravioletradiation, lipopolysaccharides and inhibitors of protein synthesis(Derijard et al., 1994, Cell 76, 1025; Han et al., 1994, Science 265,808; Raingeaud et al., 1995, J. Biol. Chem. 270, 7420; Shapiro andDinarello, 1995, Proc. Natl. Acad. Sci. USA 92, 12230). In contrast,ERKs are activated by mitogens and growth factors (Bokemeyer et al.1996, Kidney Int. 49, 1187)

[0004] ERK2 is a widely distributed protein kinase that achieves maximumactivity when both Thr183 and Tyr185 are phosphorylated by the upstreamMAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crewset al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylatesmany regulatory proteins, including the protein kinases Rsk90 (Bjorbaeket al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al.,1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaudet al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996),c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), andc-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2is also a downstream target of the Ras/Raf dependent pathways (Moodie etal., 1993, Science 260, 1658) and may help relay the signals from thesepotentially oncogenic proteins. ERK2 has been shown to play a role inthe negative growth control of breast cancer cells (Frey and Mulder,1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breastcancer has been reported (Sivaraman et al., 1997, J. Clin. Invest. 99,1478). Activated ERK2 has also been implicated in the proliferation ofendothelin-stimulated airway smooth muscle cells, suggesting a role forthis kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol.Biol. 16, 589).

[0005] The JNK family of (MAP)1 kinases have been implicated in having arole in mediating cellular response to a variety of disorders includingcancer (Oncogene 1996, 13, 135-42), hepatic disorders (Hepatology 1998,28,1022-30), cardiovascular disease (Circ. Res. 1998, 83, 167-78;Circulation 1998, 97:1731-7; J. Biol. Chem. 1997, 272, 28050-6; Circ.Res. 1996, 79, 162-73; Circ. Res. 1996, 78, 947-53; J. Clin. Invest.1996, 97, 508-14), and immunological disorders (J. Immunol. 1999, 162,3176-87; Eur. J. Immunol. 1998, 28, 3867-77; J. Exp. Med. 1997, 186,941-53; Eur. J. Immunol. 1996, 26, 989-94, among others).

[0006] Aurora2 is a serine/threonine protein kinase that has beenimplicated in human cancer, such as colon, breast and other solidtumors. This kinase is believed to be involved in proteinphosphorylation events that regulate the cell cycle. Specifically,aurora2 may play a role in controlling the accurate segregation ofchromosomes during mitosis. Misregulation of the cell cycle can lead tocellular proliferation and other abnormalities. In human colon cancertissue, the aurora2 protein has been found to be overexpressed. SeeBischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J.Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997,272, 13766-13771.

[0007] Glycogen synthase kinase-3 (GSK-3) is a serine/threonine proteinkinase comprised of α and β isoforms that are each encoded by distinctgenes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim andKimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role.

[0008] KDR is a tyrosine kinase receptor that also binds VEGF (vascularendothelial growth factor) (Neufeld et al., 1999, FASEB J., 13, 9). Thebinding of VEGF to the KDR receptor leads to angiogenesis, which is thesprouting of capillaries from preexisting blood vessels. High levels ofVEGF are found in various cancers causing tumor angiogenesis andpermitting the rapid growth of cancerous cells. Therefore, suppressingVEGF activity is a way to inhibit tumor growth, and it has been shownthat this can be achieved by inhibiting KDR receptor tyrosine kinase.

[0009] AKT, also known as protein kinase B, is a serine/threonine kinasethat plays a central role in promoting the survival of a wide range ofcell types [Khwaja, A., Nature, pp. 33-34 (1990)]. It has been shown byZang, et al, that human ovarian cancer cells display elevated levels ofAKT-1 and AKT-2. Inhibition of AKT induces apoptosis of these humanovarian cancer cells which demonstrates that AKT may be an importanttarget for ovarian cancer treatment [Zang, Q. Y., et al, Oncogene, 19(2000)]and other proliferative disorders. The AKT pathway has also beenimplicated in motoneuronal survival and nerve regeneration [Kazuhiko,N., et al, The Journal of Neuroscience, 20 (2000)].

[0010] There is a high unmet medical need to develop protein kinaseinhibitors, especially ERK inhibitors, that are useful in treating thevarious conditions associated with ERK activation, especiallyconsidering the currently available, relatively inadequate treatmentoptions for the majority of these conditions.

[0011] Accordingly, there is still a great need to develop potentinhibitors of protein kinase, including ERK inhibitors, that are usefulin treating various conditions associated with protein kinaseactivation.

DESCRIPTION OF THE INVENTION

[0012] It has now been found that compounds of this invention andcompositions thereof are effective as protein kinase inhibitors,especially as inhibitors of ERK. These compounds have the generalformula I:

[0013] or a pharmaceutically acceptable derivative thereof, wherein:

[0014] R¹ is selected from R, halogen, N(R⁸)₂, OR, NRCOR, NRCON(R⁸)₂,CON(R⁸)₂, SO₂R, NRSO₂R, or SO₂N(R⁸)₂;

[0015] T is selected from a valence bond or a linker group;

[0016] each R is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons;

[0017] R² is selected from hydrogen, CN, halogen, aryl, aralkyl,heteroaryl, heterocyclyl, an optionally substituted acyclic aliphaticchain group having one to six carbons, or an optionally substitutedcyclic aliphatic group having four to ten carbons;

[0018] R³ is selected from R, OH, OR, N(R⁸)₂, halogen, or CN;

[0019] Q is a valence bond, J, or an optionally substituted C₁₋₆alkylidene chain wherein up to two nonadjacent carbons of the alkylidenechain are each optionally and independently replaced by J;

[0020] J is selected from —C(═O)—, —CO₂—, —C(O)C(O)—, —NRCONR⁸—,—N(R)N(R⁸)—, —C(═O)NR⁸—, —NRC(═O)—, —O—, —S—, —SO—, —SO₂—, —N(R)O—,—ON(R⁸)—, —OC(═O)N(R⁸)—, —N(R)COO—, —SO₂N(R⁸)—, —N(R)SO₂—, or —N(R⁸)—;

[0021] R⁴ is selected from —R⁸, —R⁵, —NH₂, —NHR⁵, —N(R⁵)₂, or —NR⁵(CH₂)_(y)N(R⁵)₂;

[0022] each R⁵ is independently selected from R⁶, R⁷,—(CH₂)_(y)CH(R⁶)(R⁷), —(CH₂)_(y)R⁶, —(CH₂)_(y)CH(R⁶)₂,—(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷;

[0023] y is 0-6;

[0024] each R⁶ is an optionally substituted group independently selectedfrom an aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heterocycyl, heterocyclylalkyl, or heterocyclylalkoxy,group;

[0025] each R⁷ is independently selected from an optionally substitutedhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; and

[0026] each R⁸ is independently selected from R, or two R⁸ on the samenitrogen taken together with the nitrogen optionally form a four toeight membered, saturated or unsaturated heterocyclic ring having one tothree heteroatoms.

[0027] As used herein, the following definitions shall apply unlessotherwise indicated. Also, combinations of substituents or variables arepermissible only if such combinations result in stable compounds.

[0028] The term “aliphatic” as used herein means straight chained,branched or cyclic C₁-C₁₂ hydrocarbons which are completely saturated orwhich contain one or more units of unsaturation. For example, suitablealiphatic groups include substituted or unsubstituted linear, branchedor cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as.(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term“alkyl” and “alkoxy” used alone or as part of a larger moiety refers toboth straight and branched chains containing one to twelve carbon atoms.The terms “alkenyl” and “alkynyl” used alone or as part of a largermoiety shall include both straight and branched chains containing two totwelve carbon atoms. The terms “haloalkyl”, “haloalkenyl” and“haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be,substituted with one or more halogen atoms. The term “halogen” means F,Cl, Br, or I. The term “heteroatom” means N, O, or S and shall includeany oxidized form of nitrogen and sulfur, and the quaternized form ofany basic nitrogen.

[0029] The term “aryl”, used alone or as part of a larger moiety as in“aralkyl”, refers to aromatic ring groups having five to fourteenmembers, such as phenyl, benzyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and2-anthracyl, and heterocyclic aromatic groups or heteroaryl groups suchas 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4 isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl,3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, or 3-thienyl. Theterm “aryl ring” also refers to rings that are optionally substituted.

[0030] Aryl groups also include fused polycyclic aromatic ring systemsin which a carbocyclic aromatic ring or heteroaryl ring is fused to oneor more other rings. Examples include tetrahydronaphthyl,benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl,isoindolyl, acridinyl, benzoisoxazolyl, and the like. Also includedwithin the scope of the term “aryl”, as it is used herein, is a group inwhich one or more carbocyclic aromatic rings and/or heteroaryl rings arefused to a cycloalkyl or non-aromatic heterocyclic ring, for example,indanyl or tetrahydrobenzopyranyl.

[0031] Non-aromatic heterocyclic rings are non-aromatic carbocyclicrings in which one or more ring carbons are replaced by a heteroatomsuch as nitrogen, oxygen or sulfur in the ring. The ring can be five,six, seven or eight-membered and/or fused to another ring, such as acycloalkyl or aromatic ring. Examples include 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxane,benzotriazol-1-yl, benzopyrrolidine, benzopiperidine, benzoxolane,benzothiolane, and benzothiane. The term “heterocyclic ring”, whethersaturated or unsaturated, also refers to rings that are optionallysubstituted.

[0032] An aryl group (carbocyclic and heterocyclic) or an aralkyl group,such as benzyl or phenethyl, may contain one or more substituents.Examples of suitable substituents on the unsaturated carbon atom of anaryl group include a halogen, —R, —OR, —SR, protected OH (such asacyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO₂,—CN, —N(R)₂, —NRN(R)₂, —NRCON(R)₂, —NRCOR, —NRCO₂(aliphatic), —CO₂R,—COR, —C(O)C(O)R, —CON(R)₂, —CONRN(R)₂, —S(O)₂R, —SON(R)₂, —S(O)(aliphatic), —SO₂N(R)₂, or —NRS(O)₂R, where each R is independentlyselected from hydrogen, an aliphatic group or a substituted aliphaticgroup.

[0033] An aliphatic group or a non-aromatic heterocyclic ring maycontain one or more substituents. Examples of suitable substituents onthe saturated carbon of an aliphatic group or of a non-aromaticheterocyclic ring include those listed above for the unsaturated carbonas well as the following: ═O, ═S, ═NNHR, ═NNR₂, ═N—, OR, ═NNHCOR,═NNHCO₂(aliphatic), ═NNHSO₂(aliphatic), or ═NR, where each R isindependently selected from hydrogen, an aliphatic group or asubstituted aliphatic group.

[0034] The term “alkylidene chain” refers to an optionally substituted,straight or branched, carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group. Optional substituents of theC₁₋₆ alkylidine chain of Q include those described above for analiphatic group.

[0035] The term “linker group” means an organic moiety that connects twoparts of a compound. Linkers are typically comprised of an atom such asoxygen or sulfur, a unit such as —NH— or —CH₂—, or a chain of atoms,such as an alkylidene chain. The molecular mass of a linker is typicallyin the range of about 14 to 200. Examples of linkers include a saturatedor unsaturated C₁₋₆ alkylidene chain which is optionally substituted,and wherein up to two saturated carbons of the chain are optionallyreplaced by —C(═O)—, —CONH—, CONHNH—, —CO₂—, —NHCO₂—, —O—, —NHCONH—,—OC(═O)—, —OC(═O)NH—, —NHNH—, —NHCO—, —O—, —S—, —SO—, —SO₂—, —NH—,—SO₂NH—, or NHSO₂—.

[0036] It will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention.

[0037] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

[0038] One embodiment of this invention relates to compounds of formulaII:

[0039] wherein R¹, R², R³, R⁴, T, and Q are as described above.

[0040] A preferred embodiment of this invention relates to compoundshaving the formula:

[0041] wherein T, R², and R⁴ are as described above and R¹ and R³ areeach hydrogen.

[0042] Preferred compounds include those having one or more, and mostpreferably all, of the following features: (a) Q is —CO—, —CO₂—, or—CONH—; (b) T is a valence bond; (c) R¹ is hydrogen or NHR; (d) R² is anoptionally substituted aryl ring, more preferably an optionallysubstituted phenyl ring; (c) R³ is hydrogen; (e) R⁴ is selected from R⁵,—NHR⁵, —N(R⁵)₂, —NR⁵R⁶, —NHCHR⁵R⁶, or —NHCH₂R⁵; and/or (f) R⁵ is anoptionally substituted group selected from aryl, aralkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl group, (CH₂)_(y)R⁶,(CH₂)_(y)R⁷, or (CH₂)_(y)CH(R⁶)(R⁷).

[0043] Examples of substitutions of the R² phenyl group include halo,nitro, alkoxy, and amino.

[0044] When R⁴ is R⁵, examples of preferred R⁵ groups includepyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, and piperazin-1-ylwherein each group is optionally substituted. When R⁴ is —NHR⁵ or—N(R⁵)₂, preferred R⁵ groups further include (CH₂)_(y)R⁶, (CH₂)_(y)R⁷,and (CH₂)_(y)CH(R⁶)(R⁷) Examples of preferred R⁶ and R⁷ includepyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl,tetrahydrofuran-2-yl, cyclohexyl, phenyl, —CH₂OH, —(CH₂)₂ OH, andisopropyl, wherein each group is optionally substituted.

[0045] Exemplary structures of formula II, wherein R¹ and R³ are each H,are set forth in Table 1 below. TABLE 1 Compounds II II

No. T-R² Q-R⁴ II-1 phenyl CON(Me)₂ II-2 phenyl CO₂Et II-3 3-NO₂-phenylCONHNH₂ II-4 phenyl CO(pyrrolidin-1-yl) II-5 phenyl CONHCH₂(Ph) II-63-NO₂-phenyl CO₂Et II-7 4-Cl-phenyl CO₂Et II-8 4-OMe-phenyl CO₂Et II-93-NH₂-phenyl CO₂Et II-10 3-OMe-phenyl CO₂Et II-11 4-F-phenyl CO₂Et II-124-NO₂-phenyl CO₂Et II-13 3-Cl-phenyl CO₂Et II-14 3-F-phenyl CO₂Et II-15phenyl CO₂H II-16 4-NH₂-phenyl CO₂Et II-17 phenyl CONHCH₂CH₂N(Me)₂ II-18phenyl CONHCH₂(pyridin-3-yl) II-19 phenyl CO(morpholin-1-yl) II-20phenyl CONH(isopropyl) II-21 phenyl CO(4-Me-piperazin-1-yl) II-22 phenylCONHCH₂(furan-2-yl) II-23 3-OMe-phenyl CONMe₂ II-24 3-OMe-phenylCO(pyrrolidin-1-yl) II-25 3-OMe-phenyl CONHCH₂CH₂N(Me)₂ II-263-OMe-phenyl CONHCH₂(pyridin-3-yl) II-27 3-OMe-phenyl CO(morpholin-1-yl)II-28 3-OMe-phenyl CONH(isopropyl) II-29 3-OMe-phenylCO(4-Me-piperazin-1-yl) II-30 3-OMe-phenyl CONHCH₂(furan-2-yl) II-314-NH₂-phenyl CO₂Et II-32 H CONMe₂ II-33 H CO(pyrrolidin-1-yl) II-343-(AcNH)-phenyl CO₂Et II-35 4-(AcNH)-phenyl CO₂Et II-36 3-(AcNH)-phenylCO₂Et II-37 4-(AcNH)-phenyl CO₂Et II-38 3-Cl-phenyl CON(H)Bn II-393,5-Cl₂-phenyl

II-40 5-Br-phenyl CONH(3,4-F₂-phenyl) II-41 5-Cl-phenylCONH(2-OH-1-Ph-ethyl) II-42 4-OH,3-I,5-nitrophenyl CONH(2-OH-1-Ph-ethyl)II-43 5-Br-phenyl

II-44 3-NH₂, 4-OH, 5-I-phenyl CONH(2-OH-1-Ph-ethyl) II-45 5-Br-phenylCONH(2-OH-1-Ph-ethyl) II-46 5-Br-phenyl CONHCH₂(3-MeO-phenyl) II-475-Br-phenyl CONHCH₂(3-CF₃-phenyl) II-48 3,5-Cl₂-phenylCONHCH₂(pyrid-4-yl) II-49 5-CF₃-phenyl CONH(2-OH-1-Ph-ethyl) II-505-Cl-phenyl CONHCH₂Ph II-51 3,5-Cl₂-phenyl CONHOCH₂Ph II-52 4-OH, 3-I,5-nitrophenyl CONHCH₂Ph II-53 5-Cl-phenyl CONHCH₂(pyrid-4-yl) II-544,5-Cl₂-phenyl CONHOCH₂Ph II-55 5-Br-phenyl CONHCH₂(4-SO₂Me-phenyl)II-56 5-Br-phenyl CONHNH(3-CF₃-phenyl) II-57 5-Cl-phenyl CONHOCH₂PhII-58 5-Br-phenyl

II-59 5-Br-phenyl

II-60 5-Br-phenyl CONHCH₂(2-Me-phenyl) II-61 4,5-Cl₂-phenylCONHCH₂(pyrid-4-yl) II-62 5-Br-phenyl CONH(1-Ph-propyl) II-63 5-F-phenylCONHCH₂Ph II-64 4,5-Cl₂-phenyl

II-65 5-Br-phenyl

II-66 3,5-Cl₂-phenyl CON(Me)(Et) II-67 5-Cl-phenyl CONHCH₂(pyrid-3-yl)II-68 5-Br-phenyl CONHCH₂(3,5-OMe₂-phenyl) II-69 5-Br-phenylCONHCH₂(2-OMe-phenyl) II-70 4-F-5-Cl-phenyl CONHCH₂(pyrid-4-yl) II-714-F-5-Cl-phenyl CON(Me)(Et) II-72 5-Br-phenyl CONH(2-OH-1-Ph-ethyl)II-73 5-NH₂-phenyl CONHCH₂Ph II-74 4,5-Cl₂-phenyl CONHCH₂(pyrid-3-yl)II-75 5-Me-phenyl CONH(2-OH-1-Ph-ethyl) II-76 3,5-Cl₂-phenylCONHCH₂(pyrid-3-yl) II-77 4-F-5-Cl-phenyl CONHOCH₂Ph II-783,5-Cl₂-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-79 5-NO₂-phenylCONHCH₂Ph II-80 5-F-phenyl CONHCH₂(pyrid-4-yl) II-81 5-Cl-6-F-phenylCON(Me)(Et) II-82 2-F-3-Cl-phenyl CONHOCH₂Ph II-83 5-Br-phenyl

II-84 5-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-85 4,5-F₂-phenylCONHOCH₂Ph II-86 5-Br-phenyl CONH(3-OH-1-Ph-propyl) II-87 5-Br-phenyl

II-88 4,5-F₂-phenyl CONHCH₂(pyrid-4-yl) II-89 5-F-phenyl CONHOCH₂PhII-90 5-Me-phenyl CONHCH₂Ph II-91 5-Br-phenyl

II-92 4-Cl-phenyl CONHCH₂Ph II-93 5-Cl-phenyl CON(Me)(Et) II-945-Br-phenyl CONHCH_(2(4-SO) ₂NH₂-phenyl) II-95 5-OH-phenyl CONHCH₂PhII-96 5-Me-phenyl CONHCH₂(pyrid-4-yl) II-97 Phenyl CONHCH₂Ph II-982,5-F₂-phenyl CONHCH₂(pyrid-4-yl) II-99 4-Cl-phenyl CONHOCH₂Ph II-1004-F-5-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-101 4-F-5-Cl-phenylCONHCH₂(pyrid-3-yl) II-102 5-Br-phenyl CO(4-OH-4-Ph-pipexidin- 1-yl)

II-103 5,6-F₂-phenyl CONHOCH₂Ph II-104 5-Cl-phenyl CO(morpholin-1-yl)II-105 5-Br-phenyl

II-106 2-F-3-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-1074-F-5-Cl-phenyl CO(morpholin-1-yl) II-108 4-F-5-Cl-phenyl CON(Me)(Et)II-109 5-Br-phenyl CONHCH₂(4-NH₂-phenyl) II-110 5-Br-phenyl

II-111 4-F-phenyl CONHCH₂Ph II-112 3,5-Cl₂-phenyl CO(morpholin-1-yl)II-113 2,5-F₂-phenyl CONHOCH₂Ph II-114 2-F-3-Cl-phenylCONHCH₂(pyrid-3-yl) II-115 2-F-3-Cl-phenyl CONHCH₂(pyrid-4-yl) II-1164,5-F₂-phenyl CONHCH₂(pyrid-3-yl) II-117 4-OMe-phenyl CONHCH₂Ph II-1185-Br-phenyl CONHCH₂(2,4,6-OMe₃-phenyl) II-119 5-F-phenylCONHCH₂(pyrid-3-yl) II-120 4,5-F₂-phenyl CONHCH₂(tetrahydrofuran-2-yl)II-121 5-Cl-6-F-phenyl

II-122 5-Br-phenyl

II-123 5-Br-phenyl

II-124 5-Br-phenyl CONHCH₂(2,5-OMe₂-phenyl) II-125 3,5-Cl₂-phenyl

II-126 5-Br-phenyl

II-127 4,5-Cl₂-phenyl CO(morpholin-1-yl) II-128 5-Br-phenyl

II-129 2-F-3-Cl-phenyl CO(morpholin-1-yl) II-130 5-Br-phenylCONHCH₂CH₂OH II-131 5-NH₂-phenyl CONHCH₂Ph II-132 5-MeOC(O)-phenylCONHCH₂Ph II-133 4-MeO-phenyl CONHOCH₂Ph II-134 phenylCO(pyrrolidin-1-yl) II-135 5-MeO-phenyl CO(morpholin-1-yl) II-1365-Cl-phenyl CO(4-Me-piperidin-1-yl) II-137 5-NO₂-phenyl CONH₂NH₂ II-1385-Br-phenyl

II-139 5-Br-phenyl

II-140 5-Cl-phenyl CONHPh II-141 5,6-F₂-phenyl CONHCH₂(pyrid-4-yl)II-142 5-Cl-phenyl

II-143 phenyl CON(Me)₂ II-144 5-OMe-phenyl CO(pyrrolidin-1-yl) II-1455-OMe-phenyl CONHCH₂(pyrid-3-yl) II-146 4-F-phenyl CONHOCH₂Ph II-1475-OMe-phenyl CONHCH₂(furan-2-yl) II-148 5-NO₂-phenyl COOEt II-149 phenylCONHCH₂(furan-2-yl) II-150 phenyl CO(morpholin-1-yl) II-151 5-Cl-phenylCOOEt II-152 5-Br-phenyl CONHMe II-153 phenyl CONHCH₂(pyrid-3-yl) II-1545-OMe-phenyl CON(Me)₂ II-155 5-Cl-phenyl

II-156 5-Br-phenyl

II-157 5-Br-phenyl COOEt II-158 phenyl CONH(iPr) II-159 5-OMe-phenylCONH(iPr) II-160 5-COOH-phenyl CONH(iPr) II-161 5-Br-phenyl CONHO(iPr)II-162 5-F-phenyl COOEt II-163 5-OMe-phenyl CO(4-Me-piperidin-1-yl)II-164 4-NH₂-phenyl COOEt II-165 4-NO₂-phenyl COOEt II-166 phenyCO(4-Me-piperidin-1-yl) II-167 4-Cl-phenyl COOEt II-168 4-OMe-phenylCOOEt II-169 pheny COOEt II-170 5-OMe-phenyl COOEt II-171 4-F-phenylCOOEt II-172 5-NH₂-phenyl COOEt II-173 5-Cl-phenyl COOH II-1745-Cl-phenyl

II-175 5-Cl-phenyl

II-176 5-OMe-phenyl CONHCH₂(pyrid-4-yl) II-177 3,5-(OMe)₂-phenylCONHCH₂(pyrid-4-yl) II-178 4-F-phenyl CONHCH₂(pyrid-3-yl) II-1794-OMe-phenyl CONHCH₂(pyrid-3-yl) II-180 2,5-(OMe)₂-phenylCONHCH₂(pyrid-3-yl) II-181 2,5-F₂phenyl CONHCH₂(pyrid-3-yl) II-1824-F-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-183 4-OMe-phenylCONHCH₂(tetrahydrofuran-2-yl) II-184 5-F-phenylCONHCH₂(tetrahydrofuran-2-yl) II-185 5-OMe-phenylCONHCH₂(tetrahydrofuran-2-yl) II-186 2,5-(QMe)2-phenylCONHCH₂(tetrahydrofuran-2-yl) II-187 5,6-F₂-phenylCONHCH₂(tetrahydrofuran-2-yl) II-188 2,5-F₂-phenylCONHCH₂(tetrahydrofuran-2-yl) II-189 4-F-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-190 4-OMe-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-191 5-F-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-192 5-OMe-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-193 3,6-(OMe)₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-194 4,5-F₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-195 5,6-F₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-196 3,6-F₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-197 4-F-phenyl CO(morpholin-1-yl)II-198 4-OMe-phenyl CO(morpholin-1-yl) II-199 5-F-phenylCO(morpholin-1-yl) II-200 2,5-(OMe)₂-phenyl CO(morpholin-1-yl) II-2014,5-F₂-phenyl CO(morpholin-1-yl) II-202 5,6-F₂-phenyl CO(morpholin-1-yl)II-203 2,5-F₂-phenyl CO(morpholin-1-yl) II-204 4-F-phenylCO(4-Me-piperidin-1-yl) II-205 4-OMe-phenyl CO(4-Me-piperidin-1-yl)II-206 5-F-phenyl CO(4-Me-piperidin-1-yl) II-207 2,5-(OMe)₂-phenylCO(4-Me-piperidin-1-yl) II-208 4,5-F₂-phenyl CO(4-Me-piperidin-1-yl)II-209 5,6-F₂-phenyl CO(4-Me-piperidin-1-yl) II-210 3,6-F₂-phenylCO(4-Me-piperidin-1-yl) II-211 4-Cl-phenyl CONHCH₂(pyrid-4-yl) II-2124,5-(OMe)₂-phenyl CONHCH₂(pyrid-4-yl) II-213 4-benzo[1,3]dioxo-5-ylCONHCH₂(pyrid-4-yl) II-214 4-Cl-phenyl CONHCH₂(pyrid-3-yl) II-2154,5-(OMe)₂-phenyl CONHCH₂(pyrid-3-yl) II-216 4-benzo[1,3]dioxo-5-ylCONHCH₂(pyrid-3-yl) II-217 4-Cl-phenyl CONHCH₂(tetrahydrofuran-2-yl)II-218 4,5-(OMe)₂-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-2194-benzo[1,3]dioxo-5-yl CONHCH₂(tetrahydrofuran-2-yl) II-220 4-Cl-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-221 4,5-Cl₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-222 5-Cl-6-F-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-223 4-F-5-Cl-phenylCONHCH₂(1-Et-prrrolidin-2-yl) II-224 4,5-(OMe)₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-225 4-benzo[1,3]dioxo-5-ylCONHCH₂(1-Et-pyrrolidin-2-yl) II-226 3,5-Cl₂-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-227 4-Cl-phenyl CO(morpholin-1-yl)II-228 4,5-(OMe)₂-phenyl CO(morpholin-1-yl) II-2294-benzo[1,3]dioxo-5-yl CO(morpholin-1-yl) II-230 4-Cl-phenylCO(4-Me-piperidin-1-yl) II-231 4,5-Cl₂-phenyl CO(4-Me-piperidin-1-yl)II-232 5-Cl-6-F-phenyl CO(4-Me-piperidin-1-yl) II-233 4-F-5-Cl-phenylCO(4-Me-piperidin-1-yl) II-234 4,5-(OMe)₂-phenyl CO(4-Me-piperidin-1-yl)II-235 4-benzo[1,3]dioxo-5-yl CO(4-Me-piperidin-1-yl) II-2363,5-Cl₂-phenyl CO(4-Me-piperidin-1-yl) II-237 5,6-F₂-phenyl CON(Me)(Et)II-238 4-F-phenyl

II-239 5-OMe-phenyl

II-240 2,5-(OMe)₂-phenyl

II-241 4,5-F₂-phenyl

II-242 5,6-F₂-phenyl

II-243 3,6-F₂-phenyl

II-244 5-MeO-phenyl CONHOCH₂Ph II-245 2,5-(OMe)₂-phenyl CONHOCH₂PhII-246 5-F-phenyl

II-247 5-MeO-phenyl

II-248 4,5-F₂-phenyl

II-249 5,6-F₂-phenyl

II-250 5-Cl-phenyl

II-251 4-Cl-phenyl

II-252 4-Cl-phenyl

II-253 4,5-Cl₂-phenyl

II-254 4,5-Cl₂-phenyl

II-255 2-F-3-Cl-phenyl

II-256 4-F-5-Cl-phenyl

II-257 4-F-5-Cl-phenyl

II-258 4,5-(OMe)₂-phenyl CON(Me)(Et) II-259 4,5-(OMe)₂-phenyl

II-260 4,5-(OMe)₂-phenyl CONHOCH₂Ph II-261 4,5-(OMe)₂-phenyl

II-262 4-benzo[1,3]dioxo-5-yl CON(Me)(Et) II-263 4-benzo[1,3]dioxo-5-yl

II-264 4-benzo[1,3]dioxo-5-yl CONHOCH₂Ph II-265 4-benzo[1,3]dioxo-5-yl

II-266 3,5-Cl₂-phenyl

II-267 5-Br-phenyl

II-268 5-Br-phenyl

II-269 5-Br-phenyl

II-270 5-Br-phenyl

II-271 5-Br-phenyl

II-272 5-Br-phenyl

II-273 5-Br-phenyl

II-274 5-Br-phenyl

II-275 5-Br-phenyl

II-276 5-Br-phenyl

II-277 5-Br-phenyl

II-278 5-Br-phenyl

II-279 5-Br-phenyl

II-280 5-Br-phenyl CONH(CH₂)₂COOH II-281 5-Br-phenyl

II-282 5-Br-phenyl CONHCH₂(4-COOH-phenyl) II-283 5-Br-phenyl

II-284 5-Br-phenyl

II-285 3-NO₂-phenyl CONHCH₂phenyl II-286 5-Cl-phenylCONHCH₂(1-Et-pyrrolidin-2-yl) II-287 5-(N-Et-NHCO)-phenyl CONHCH₂phenylII-288 5-Br-phenyl

II-289 5-NO₂-phenyl CONHCH₂(pyrid-4-yl) II-290 5-Br-phenyl

II-291 5-F-phenyl CON(Me)(Et) II-292 5-MeO-phenyl CON(Me)(Et) II-2935-Br-phenyl

II-294 5-Br-phenyl

II-295 5-Br-phenyl

II-296 5-Br-phenyl

II-297 phenyl CONH(CH₂)₂NMe₂ II-298 5-MeO-phenyl CONH(CH₂)₂NMe₂ II-2995-Br-phenyl CONHCH₂phenyl II-300 3-Cl-phenyl

II-301 3-Cl-phenyl

II-302 3-Cl-phenyl

II-303 3-Cl-phenyl

II-304 3-Cl-phenyl

II-305 3-Cl-phenyl

II-306 3-Cl-phenyl

II-307 3-Cl-phenyl

II-308 3-Cl-phenyl

II-309 3-Cl-phenyl

II-310 3,5-Cl₂-phenyl

II-311 3-Br-5-CF₃-phenyl

II-312 3-Cl-phenyl

II-313 3,5-Cl₂-pbenyl

II-314 3-Cl-4-CN-phenyl

II-315 3-Cl-4-CH₂OH-phenyl

II-316 3-Cl-4-CH₂NH₂-phenyl

II-317

II-318

II-319

II-320

II-321

II-322

II-323 CH₂Ph CON(Me)₂ II-324 cyclopentylmethyl CO₂NHCH₂Ph II-325isopropyl CN II-326 3-Cl-phenyl NHCOCH₂Ph II-327 3-Cl-phenylNHSO₂-morpholin-1-yl II-328 3-Cl-phenyl NHCONHCH₂Ph II-329 3-Cl-phenylNHCO₂-tetrahydrofuran-2-yl II-330 CH₂Ph CONHCH₂Ph II-331 Me CONHCH₂PhII-332 isopropyl CONHCH₂Ph II-333 H CON(Me)₂

[0046] Another preferred embodiment of this invention relates tocompounds of formula II-B:

[0047] wherein T, R, R², and R⁴ are as described above.

[0048] Preferred II-B compounds include those having one or more, andmost preferably all, of the following features: (a) T is a valence bond;(b) R³ is hydrogen; and/or (c) R₂ is an optionally substituted arylring, more preferably an optionally substituted phenyl ring.

[0049] Exemplary structures of formula II-B, wherein R³ is H, are setout in Table 2 below. TABLE 2 Compounds II-B No. R T-R² Q-R⁴ II-B-1 Hphenyl CON(Me)₂ II-B-2 H phenyl CO₂Et II-B-3 H 3-NO₂-phenyl CONHNH₂II-B-4 H phenyl CO(pyrrolidin-1-yl) II-B-5 Me phenyl CONHCH₂(Ph) II-B-6H 3-NO₂-phenyl CO₂Et II-B-7 H 4-Cl-phenyl CO₂Et II-B-8 Me 4-OMe-phenylCO₂Et II-B-9 H 3-NH₂-phenyl CO₂Et II-B-10 H 3-OMe-phenyl CO₂Et II-B-11 H4-F-phenyl CO₂Et II-B-12 H 4-NO₂-phenyl CO₂Et II-B-13 Et 3-Cl-phenylCO₂Et II-B-14 H 3-F-phenyl CO₂Et II-B-15 H phenyl CO₂H II-B-16 Me3-Cl-phenyl CONHCH₂(pyridin-4-yl) II-B-17 H 5-Cl-phenyl

II-B-18 H 5-F-phenyl CONHCH₂(tetrahydrofuran-2-yl) II-B-19 Me5,6-F₂-phenyl CO(4-Me-piperidin-1-yl) II-B-20 H 4-Cl-phenylCONHCH₂(pyrid-4-yl) II-B-21 H 4,5-(OMe)₂-phenyl

II-B-22 Me 4,5-Cl₂-phenyl

II-B-23 H 3-Cl-phenyl

II-B-24 H 3-Cl-phenyl

II-B-25 Me 3,5-Cl₂-phenyl

II-B-26 H

II-B-27 H H CON(Me)₂

[0050] The present compounds may be prepared in general by methods knownto those skilled in the art for analogous compounds, as illustrated bythe general Schemes I and II and the synthetic examples shown below.

[0051] Scheme I above shows a general synthetic route that was used forpreparing the compounds of this invention when R² is an optionallysubstituted phenyl group. In step (a), an optionally substituted benzoylchloride was combined with compound 1 in dichloromethane and aluminumtrichloride to form compound 2. A wide variety of substitutions on thephenyl ring are amenable to this reaction. Examples of suitable R²groups include, but are not limited to, those set forth in Table 1above.

[0052] The formation of amide 4 was achieved by treating compound 2 withan amine 3 in DMF. When amine 3 was a primary amine, the reactionproceeded at ambient temperature. When amine 3 was a secondary amine,the reaction was heated at 50° C. to achieve complete reaction andafford amide 4.

[0053] The formation of enamine 5 at step (c) was achieved by treatingamide 4 with (Me₂N)₂—Ot—Bu at ambient temperature. Alternatively, thereaction to form enamine 5 at step (c) was also achieved by usingdimethylformamide-dimethylacetal (DMF-DMA). The reaction using DMF-DMArequires elevated temperature to afford enamine 5 whereas using(Me₂N)₂—OtBu has the advantage of proceeding at ambient temperature toafford the enamine 5 in higher purity.

[0054] The formation of the pyrazole compound 6 at step (d) was achievedby the treatment of enamine 5 with hydrazine hydrate at elevatedtemperature. The compounds of formula II synthesized by this method, asexemplified in Table 1, were isolated by preparatory HPLC (reversephase, 10→90% MeCN in water over 15 minutes). The details of theconditions used for producing these compounds are set forth in theExamples.

[0055] Scheme II above shows a general synthetic method that may be usedfor preparing compounds of formula II-B, using compound II-B-16 as anexample. This method is modified from that of Jira, T., et al,Pharmazie, pp. 401-406 (1994). Compounds of formula II-B may also beprepared by methods similar to those of Woller, J., et al, Pharmazie,pp. 937-940 (1996), Rychmans, T., et al, Tetrahedron, pp. 1729-1734(1997), and Tupper, D. E., et al, Synthesis, pp. 337-341 (1997).

[0056] According to another embodiment, the invention provides a methodof inhibiting kinase activity in a biological sample. This methodcomprises the step of contacting said biological sample with a compoundof this invention.

[0057] The term “biological sample”, as used herein includes cellcultures or extracts thereof; biopsied material obtained from a mammalor extracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof. The term “biological sample” alsoincludes living organisms, in which case “contacting a compound of thisinvention with a biological sample” is synonymous with the term“administrating said compound (or composition comprising-said compound)to a mammal.”

[0058] Another aspect of this invention relates to a method for treatinga disease state in mammals that is alleviated by treatment with aprotein kinase inhibitor, which method comprises administering to amammal in need of such a treatment a therapeutically effective amount ofa compound having the formula

[0059] or a pharmaceutically acceptable derivative thereof, wherein:

[0060] R¹ is selected from R, halogen, N(R⁸)₂, OR, NRCOR, NRCON(R⁸)₂,CON(R⁸)₂, SO₂R, NRSO₂R, or SO₂N(R⁸)₂;

[0061] T is selected from a valence bond or a linker group;

[0062] each R is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons;

[0063] R² is selected from hydrogen, CN, halogen, aryl, aralkyl,heteroaryl, heterocyclyl, an optionally substituted acyclic aliphaticchain group having one to six carbons, or an optionally substitutedcyclic aliphatic group having four to ten carbons;

[0064] R³ is selected from R, OH, OR, N(R⁸)₂, halogen, or CN;

[0065] Q is a valence bond, J, or an optionally substituted C₁₋₆alkylidene chain wherein up to two nonadjacent carbons of the alkylidenechain are each optionally and independently replaced by J;

[0066] J is selected from —C(═O)—, —CO₂—, —C(O)C(O)—, —NRCONR⁸—,—N(R)N(R⁸)—, —C(═O)NR⁸—, —NRC(═O)—, —O—, —S—, —SO—, —SO₂—, —N(R)O—,—ON(R⁸)—, —OC(═O)N(R⁸)—, —N(R)COO—, —SO₂N(R⁸)—, —N(R)SO₂—, or —N(R⁸)—;

[0067] R⁴ is selected from —R⁸, —R⁵, —NH₂, —NHR⁵, —N(R⁵)₂, or —NR⁵(CH₂)_(y)N(R⁵)₂;

[0068] each R⁵ is independently selected from R⁶, R⁷,—(CH₂)_(y)CH(R⁶)(R⁷), —(CH₂)_(y)R⁶, —(CH₂)_(y)CH(R⁶)₂,—(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷;

[0069] y is 0-6;

[0070] each R⁶ is an optionally substituted group independently selectedfrom an aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, orheterocyclylalkoxy, group;

[0071] each R⁷ is independently selected from an optionally substitutedaliphatic, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl;

[0072] and each R⁸ is independently selected from R, or two R⁸ on thesame nitrogen taken together with the nitrogen optionally form a four toeight membered, saturated or unsaturated heterocyclic ring having one tothree heteroatoms.

[0073] One embodiment comprises administering a compound of formula II.A preferred embodiment comprises administering a compound of formulaII-A, and most preferably a compound listed in Table 1. Anotherpreferred embodiment comprises administering a compound of formula II-B,and more preferably a compound listed in Table 2. Pharmaceuticalcompositions useful for such methods are described below.

[0074] The present method is especially useful for treating a diseasestate that is alleviated by the use of an inhibitor of ERK, JAK, JNK,Aurora, GSK, KDR, or AKT. As used herein, unless otherwise indicated,the terms “ERK”, “JAK”, “JNK”, “Aurora”, “GSK”, “KDR”, and “AKT” referto all isoforms of the respective enzymes including, but not limited to,ERK1, ERK2, ERK3, ERK4, ERK5, ERK6, ERK7, JAK1, JAK2, JAK3, JAK4, JNK1,JNK2, JNK3, Aurora1, Aurora2, GSK3-alpha, GSK3-beta, KDR, AKT1, AKT-2,and AKT-3.

[0075] The activity of the compounds as protein kinase inhibitors, forexample as ERK inhibitors, may be assayed in vitro, in vivo or in a cellline. Using ERK as an example, in vitro assays include assays thatdetermine inhibition of either the kinase activity or ATPase activity ofactivated ERK. Alternate in vitro assays quantitate the ability of theinhibitor to bind to ERK and may be measured either by radiolabellingthe inhibitor prior to binding, isolating the inhibitor/ERK complex anddetermining the amount of radiolabel bound, or by running a competitionexperiment where new inhibitors are incubated with ERK bound to knownradioligands. One may use any type or isoform of ERK, depending uponwhich ERK type or isoform is to be inhibited.

[0076] The compounds of this invention are potent inhibitors of ERK asdetermined by enzymatic assay. These compounds have also been shown toinhibit ERK in a cell proliferation assay. The details of the conditionsused for both the enzymatic and the cell proliferation assays are setforth in the Examples hereinbelow.

[0077] The compounds of this invention are also inhibitors of JNK,Aurora, GSK, KDR, and AKT as determined by enzymatic assay. The detailsof the conditions used for this assay are set forth in the Exampleshereinbelow. Without being bound by theory, the compounds of thisinvention are also expected to inhibit other protein kinases.

[0078] The protein kinase inhibitors of this invention, orpharmaceutical salts thereof, may be formulated into pharmaceuticalcompositions for administration to animals or humans. Thesepharmaceutical compositions effective to treat or prevent a proteinkinase-mediated condition which comprise the protein kinase inhibitor inan amount sufficient to detectably inhibit protein kinase activity and apharmaceutically acceptable carrier, are another embodiment of thepresent invention. The term “detectably inhibit”, as used herein means ameasurable change in activity between a sample containing said inhibitorand a sample containing only a protein kinase.

[0079] The term “ERK-mediated condition”, as used herein means anydisease state or other deleterious condition in which ERK is known toplay a role. Such conditions include, without limitation, cancer,stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases. The term “cancer” includes, but is not limitedto the following cancers: breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon,adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colon-rectum, large intestine, rectum, brain andcentral nervous system, and leukemia.

[0080] Compounds of the present invention are also useful as inhibitorsof related kinases. The term “related kinases” refer to protein kinaseshaving residues which are similar to those residues which line the ERKbinding site. Without wishing to be bound by theory, applicantsspeculate that this inhibitory activity is due to the close structuralsimilarity between the active sites of ERK and related kinases. Thealignment of the ERK sequence with other kinases can be derived fromcommon software programs such as the “bestfit” program available fromGenetics Computer Group. This program uses the local homology algorithmdescribed by Smith and Waterman in Advances in Applied Mathematics 2;482 (1981).

[0081] Related kinases inhibited by the compounds of this inventionwould contain residues, identified by the above standard proteinsequence alignment software, corresponding to the ERK residues: 131,E33, G34, A35, Y36, G37, M38, V39, A52, K54, R67, T68, E71, L75, 184,186, 1103, Q105, D106, L107, M108, E109, D111, K114, D149, K151, S153,N154, L156, C166, and D167, with a similarity score of 80% or greater.The similarity score may be determined using standard amino acidsubstitution tables such as those described by Dayhoff (Dayhoff, M. O.,et al, Atlas of Protein Sequence and Structure, 1979) andBlosom-Henikoff (Blosum-Henikoff, S and Henikoff, J. G., PNAS,1992,89:10915-10919). The term “related kinases” also includes thosecontaining residues with a similarity score of 80% or greater to thefollowing ERK residues: 131, G37, A52, I103, E109, and N154.

[0082] Compounds of the present invention are also useful as inhibitorsof JAK-family kinases. Without wishing to be bound by theory, applicantsspeculate that this inhibitory activity is due to the close structuralsimilarity between the active sites of ERK and JAK as determined by thestandard methods described above.

[0083] It has been found, from in-house x-ray crystal structureexperiments with ERK-bound inhibitors, that three amino-acid residues inthe ERK active site form key hydrogen bonding interactions with thesetypes of inhibitors. These three amino-acid residues are M108, D106, andQ105. This amino acid numbering corresponds to the Swiss-Prot databaseentry for accession #P28482. The Swiss-Prot database is an internationalprotein sequence database distributed by the European Bioinformatics.Institute (EBI) in Geneva, Switzerland. The database can be found atwww.ebi.ac.uk/swissprot.

[0084] The backbone atoms of M108 and D106, and the associatedinteractions, are common to all kinases. M108 provides both a hydrogenbond donor and acceptor and D106 provides a hydrogen bond acceptorthrough its backbone CO. An inhibitor that could form a hydrogen-bond toone or more of these hydrogen-bonding groups within the active sitewould be expected to bind to the enzyme and, therefore, show inhibition.

[0085] The Q105 glutamine residue is implicated in a subset of kinasesthat includes ERK and JAK as determined by examination of the alignmentdata obtained from the above mentioned software programs. Q105 providesa key hydrogen-bond accepting side-chain CO. Modeling experiments revealthat for both ERK and JAK, the hydrogen bond donor of the Ht-ring iswithin hydrogen-bonding distance to the Q105 residue. Because of thesesimilar active-site interactions, the ERK inhibitors of the presentinvention inhibit JAK as well. Accordingly, these compounds are usefulfor treating JAK-mediated conditions.

[0086] The term “JAK-mediated condition”, as used herein, means anydisease state or other deleterious condition in which JAK is known toplay a role. Such conditions include, without limitation, allergicdisorders such as asthma and atopic dermatitis, autoimmune diseases suchas SLE lupus and psoriasis, and conditions associated with organtransplantations.

[0087] The compounds of this invention are also useful as inhibitors ofJNK-family kinases. Accordingly, these compounds are useful for treatingJNK-mediated conditions. The term “JNK-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichJNK is known to play a role. Such conditions include, withoutlimitation, apoptosis-driven neurodegenerative diseases such asAlzheimer's Disease, Parkinson's Disease, ALS (Amyotrophic LateralSclerosis), epilepsy and seizures, Huntington's Disease, traumatic braininjuries, as well as ischemic and hemorrhaging stroke, heart disease,immunodeficiency disorders, inflammatory diseases, allergic disorders,autoimmune diseases, destructive bone disorders such as osteoporosis,proliferative disorders, infectious diseases, viral diseases, disordersrelating to cell death and hyperplasia including reperfusion/ischemia instroke, heart attacks, and organ hypoxia, thrombin-induced plateletaggregation, chronic myelogenous leukemia (CML), rheumatoid arthritis,asthma, osteoarthritis, ischemia, cancer, liver disease includinghepatic ischemia, heart disease such as myocardial infarction andcongestive heart failure, pathologic immune conditions involving T cellactivation and neurodegenerative disorders.

[0088] The compounds of this invention are also useful as inhibitors ofAurora. Accordingly, these compounds are useful for treatingAurora-mediated conditions. The term “Aurora-mediated condition”, asused herein, means any disease or other deleterious condition in whichAurora is known to play a role. Such conditions include, withoutlimitation, cancer. The term “cancer” includes, but is not limited tothe following cancers: colon and ovarian.

[0089] The compounds of this invention are also useful as inhibitors ofGSK family kinases. Accordingly, these compounds are useful for treatingGSK-mediated conditions. The term “GSK-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichGSK is known to play a role. Such conditions include, withoutlimitation, diabetes, Alzheimers disease, neurodegenerative diseases,and CNS disorders such as manic depressive disorder and schizophrenia.

[0090] The compounds of this invention are also useful as inhibitors ofKDR family kinases. Accordingly, these compounds are useful for treatingKDR-mediated conditions. The term “KDR-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichKDR is known to play a role. KDR-mediated diseases or conditionsinclude, but are not limited to, cancer such as brain cancer,genitourinary tract cancer, lymphatic system cancer, stomach cancer,cancer of the larynx, lung cancer, pancreatic cancer, breast cancer,Kaposi's sarcoma, and leukemia; endometriosis, benign prostatichyperplasia; vascular diseases such as restenosis and atherosclerosis;autoimmune diseases such as rheumatoid arthritis and psoriasis; ocularconditions such as proliferative or angiogenic retinopathy and maculardegeneration; and inflammatory diseases such as contact dermatitis,asthma and delayed hypersensitivity reactions.

[0091] The compounds of this invention are also useful as inhibitors ofAKT family kinases. Accordingly, these compounds are useful for treatingAKT-mediated conditions. The term “AKT-mediated condition”, as usedherein, means any disease state or other deleterious condition in whichAKT is known to play a role. AKT-mediated diseases or conditionsinclude, but are not limited to, proliferative disorders, cancer, andneurodegenerative disorders.

[0092] In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified disorders.

[0093] A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a mammal (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

[0094] Pharmaceutically acceptable prodrugs of the compounds of thisinvention include, without limitation, esters, amino acid esters,phosphate esters, metal salts and sulfonate esters.

[0095] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylssulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate., tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0096] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quaternization.

[0097] Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

[0098] The compositions of the present invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

[0099] Sterile injectable forms of the compositions of this inventionmay be aqueous or an oleaginous suspension. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

[0100] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

[0101] Alternatively, the pharmaceutical compositions of this inventionmay be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient which is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0102] The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

[0103] Topical application for the lower intestinal tract can beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0104] For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

[0105] For ophthalmic use, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment such as petrolatum.

[0106] The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

[0107] The amount of protein kinase inhibitor of this invention that maybe combined with the carrier materials to produce a single dosage formwill vary depending upon the host treated, the particular mode ofadministration. Preferably, the compositions should be formulated sothat a dosage of between about 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

[0108] It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

[0109] The kinase inhibitors of this invention or pharmaceuticalcompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Vascular stents, forexample, have been used to overcome restenosis (re-narrowing of thevessel wall after injury). However, patients using stents or otherimplantable devices risk clot formation or platelet activation. Theseunwanted effects may be prevented or mitigated by pre-coating the devicewith a composition comprising a kinase inhibitor. Suitable coatings andthe general preparation of coated implantable devices are described inU.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.Implantable devices coated with a kinase inhibitor of this invention areanother embodiment of the present invention.

[0110] According to another embodiment, the invention provides methodsfor treating or preventing an ERK-, JAK-, JNK-, Aurora-, GSK-, KDR-, orAKT-mediated condition, or disease state, comprising the step ofadministering to a patient one of the above-described pharmaceuticalcompositions. The term “patient”, as used herein, means a mammal,preferably a human.

[0111] Preferably, that method is used to treat or prevent a condition,or disease state, selected from cancers such as cancers of the breast,colon, prostate, skin, pancreas, brain, genitourinary tract, lymphaticsystem, stomach, larynx and lung, including lung adenocarcinoma andsmall cell lung cancer, stroke, diabetes, hepatomegaly, cardiomegaly,cardiovascular disease, Alzheimer's disease, cystic fibrosis, and viraldisease, or any specific disease or disorder described above.

[0112] Depending upon the particular condition, or disease state, to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example,chemotherapeutic agents or other antiproliferative agents may becombined with the inhibitors of this invention to treat proliferativediseases and cancer. Examples of known chemotherapeutic agents include,but are not limited to, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives.

[0113] Other examples of agents the inhibitors of this invention mayalso be combined with include, without limitation, anti-inflammatoryagents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; agents for treating diabetessuch as insulin, insulin analogues, alpha glucosidase inhibitors,biguanides, and insulin sensitizers; and agents for treatingimmunodeficiency disorders such as gamma globulin.

[0114] These additional agents may be administered separately, as partof a multiple dosage regimen, from the inhibitor-containing composition.Alternatively, these agents may be part of a single dosage form, mixedtogether with the inhibitor in a single composition.

[0115] In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Example 1

[0116]

[0117] 2,2,2-Trichloro-1-(4-phenylacetyl-1H-pyrrol-2-yl)ethanone (1): Ina dry flask, phenylacetyl chloride (1 equivalent) was combined with2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount ofdichloromethane (DCM). To the resulting solution, at ambienttemperature, was added aluminum trichloride (1 equivalent). After 2hours, the reaction mixture was applied directly onto a silica gelcolumn. Gradient elution with 10% ethyl acetate to 50% ethyl acetate inhexanes provided compound 1 in 60% yield. ¹H NMR (CDCl₃) δ 4.0 (s, 2H),7.1-7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B (as describedbelow for Example 5) provided retention time of 4.9 minutes. LC/MS (M+1)330.2, (M−1) 328.1.

Example 2

[0118]

[0119] 4-Phenylacetyl-1H-pyrrole-2-carboxylic acid benzylamide (2): To asolution of compound 1 (1 equivalent) in DMF, at ambient temperature,was added benzylamine (1.2 equivalents). After 24 hours, the solvent wasevaporated and the crude product 2 was utilized without purification.HPLC using method B (as described below for Example 5) providedretention time of 3.8 minutes. FIA/MS (M+1) 319.3, (M−1) 317.2.

Example 3

[0120]

[0121] 4-(3-Dimethylamino-2-phenyl-acryloyl)-1H-pyrrole-2-carboxylicacid benzylamide (3): To a solution of compound 2 (1 equivalent) in THF,at ambient temperature, was added (Me₂N)₂CHOt-Bu (3 equivalents). After24 hours, the solvent was evaporated and the crude product 3 wasutilized without purification. ¹H NMR (CDCl₃) δ 4.4 (s, 2H), 4.8 (s,NH), 6.8-7.4 (m, 13H).

Example 3

[0122]

[0123] 4-(4-phenyl-1H-pyrazole-3-yl)-1H-pyrrole-2-carboxylic acidbenzylamide (II-5): To a solution of compound 3 (1 equivalent) inethanol, at ambient temperature, was added hydrazine hydrate (3equivalents) and the resulting mixture heated at reflux. After 12 hours,the solvent was evaporated and the crude product purified by preparatoryHPLC (reverse phase; 10→90% MeCN in water; 15 minutes) to afford thedesired compound II-5. LC/MS (M+1) 343.3, (M−1) 341.2.

Example 5

[0124] We have prepared other compounds of formula II by methodssubstantially similar to those described in the above Examples 1-4 andthose illustrated in Scheme I. The characterization data for thesecompounds is summarized in Table 3 below and includes LC/MS, HPLC, and¹H NMR data.

[0125] For compounds where the HPLC Method is designated as “A”, thefollowing method was utilized: a gradient of water:MeCN, 0.1% TFA(95:5→0:100) was run over 22 minutes at 1 mL/min and 214 nm. Forcompounds where the HPLC Method is designated as “B”, the followingmethod was utilized: a gradient of water:MeCN, 0.1% TFA (90:10→0:100)was run over 8 minutes at 1 mL/min and 214 nm. Each of methods A and Butilize the YMC ODS-AQ 55 120A column with a size of 3.0×150 mm. Theterm “T_(ret)(min)” refers to the retention time, in minutes, associatedwith the compound using the designated HPLC method.

[0126] Where applicable, ¹H NMR data is also summarized in Table 3 belowwherein “Y” designates ¹H NMR data is available and was found to beconsistant with structure. Compound numbers correspond to the compoundnumbers listed in Table 1. TABLE 3 Characterization Data for SelectedCompounds Compound No M + 1 M − 1 HPLC Method T_(ret) (min) ¹H NMR II-41407.4 405.4 A 8.6 Y II-42 560.2 558.1 A 9.5 — II-43 — — A 10.5 — II-44530.3 528.2 A 6.3 — II-45 — — A 9.8 — II-46 — — A 10.6 — II-50 377.4 — A10.1 Y II-52 530.2 528.2 A 10.3 — II-53 378.4 376.3 A 7.4 Y II-56 490.2488.1 A 10.8 — II-58 — — A 10.46 — II-59 — — A 9.1 — II-63 361.4 359.3 A9.5 Y II-65 — — A 10.0 — II-67 378.4 376.3 A 7.4 Y II-72 451.5 449.1 A10.15 Y II-80 374.4 372.3 A 6.6 — II-83 435.3 433.4 A 10.3 — II-85 — — A10.6 — II-86 — — A 9.3 — II-88 380.4 378.3 A 6.9 — II-89 — — A 10.5 —II-91 — — A 9.6 — II-92 377.4 375.3 A 10.2 Y II-94 — — A 9.0 — II-97342.1 — B 3.8 Y II-98 380.4 378.3 A 6.7 — II-102 — — A 10.3 — II-103 — —A 10.6 — II-105 — — A 9.3 — II-109 — — A 7.9 — II-110 — — A 10.3 —II-111 361.4 359.3 A 9.4 Y II-113 — — A 10.6 — II-116 380.2 378.4 A 6.9— II-117 373.4 — A 9.0 Y II-119 362.4 371.4 A 6.5 — II-120 373.4 371.4 A8.2 — II-122 — — A 10.8 — II-123 — — A 11.4 — II-126 — — A 10.2 — II-128— — A 10.9 — II-130 — — A 7.4 — II-133 — — A 9.5 — II-134 306.1 — B 3.5Y II-135 353.4 351.4 A 7.7 — II-137 313.3 311.2 A 6.4 Y II-141 380.4378.3 A 6.7 — II-143 280.1 — B 3.3 Y II-144 336.4 — B 3.5 — II-145 373.4— B 2.8 — II-146 — — A 10.5 — II-147 362.4 — B 3.5 — II-148 327.3 325.2A 9.2 Y II-149 332.4 — B 3.5 — II-150 322.4 — B 3.2 — II-151 316.2 314.2A 10.3 Y II-152 — — A 6.6 — II-153 323.4 — B 2.3 — II-154 343.4 — B 2.8— II-158 294.3 — B 3.4 — II-159 335.4 — B 2.7 — II-161 389.3 387.2 A 8.9— II-162 300.3 298.2 A 9.5 Y II-163 366.5 364.4 B 6.0 — II-164 297.3 — A5.1 Y II-165 322.3 325.2 A 9.7 Y II-167 316.2 314.2 A 10.0 Y II-168312.3 310.2 A 8.6 Y II-169 281.1 — B 3.9 Y II-170 312.3 310.2 A 9.1 YII-171 300.3 298.2 A 9.4 Y II-172 297.3 295.7 A 5.5 Y II-174 449.3 447.2A 12.5 Y II-175 477.3 475.3 A 14.0 Y II-176 374.4 372.4 A 6.3 — II-178362.4 360.0 A 6.6 — II-179 374.4 372.4 A 6.3 — II-180 404.4 402.4 A 6.4— II-181 380.2 378.3 A 6.7 — II-182 355.4 353.4 A 7.7 — II-183 367.4365.4 A 7.4 — II-184 355.4 353.4 A 7.9 — II-185 367.4 365.3 A 7.5 —II-186 397.4 395.4 A 7.1 — II-187 373.4 371.4 A 8.0 — II-188 373.4 371.4A 7.9 — II-189 382.4 380.4 A 6.9 — II-190 394.4 392.4 A 6.7 — II-191382.4 380.4 A 7.0 — II-192 394.5 392.4 A 6.7 — II-193 424.4 422.4 A 6.4— II-194 400.4 398.4 A 7.3 — II-195 400.4 398.4 A 7.1 — II-196 400.4398.4 A 7.2 — II-197 341.3 339.2 A 7.5 — II-198 353.4 351.4 A 7.1 —II-199 341.3 339.2 A 7.6 — II-200 383.4 381.4 A 6.9 — II-201 359.4 357.4A 8.0 — II-202 359.4 357.4 A 7.8 — II-203 359.4 357.4 A 7.7 — II-204354.4 352.4 A 6.2 — II-205 366.4 364.4 A 5.9 — II-206 354.4 .52.4 A 5.6— II-207 396.4 394.4 A 5.9 — II-208 372.4 370.4 A 6.7 — II-209 372.4370.4 A 6.5 — II-210 372.4 370.4 A 6.4 — II-237 — — A 9.8 — II-238 — — A11.6 — II-239 — — A 11.3 — II-240 — — A 7.5 — II-241 — — A 12.0 — II-242— — A 11.7 — II-243 — — A 11.6 — II-244 389.4 387.3 A 10.2 — II-245 — —A 10.6 — II-246 365.4 363.4 A 7.5 — II-247 — — A 7.2 — II-248 — — A 8.0— II-249 — — A 7.7 — II-267 — — A 10.7 — II-268 — — A 10.0 — II-269 — —A 12.2 — II-270 — — A 12.3 — II-271 — — A 9.3 — II-272 — — A 12.7 —II-273 — — A 12.7 — II-274 — — A 3.8 — II-275 — — A 10.3 — II-276 — — A8.4 — II-277 — — A 10.6 — II-278 — — A 12.8 — II-279 — — A 11.4 — II-280— — A 7.9 — II-281 — — A 11.5 — II-282 — — A 8.6 — II-283 — — A 8.4 —II-284 — — A 12.2 — II-290 — — A 11.4 — II-291 — — A 9.7 — II-292 — — A9.1 — II-293 481.3 479.3 A 8.3 — II-294 455.4 453.3 A 6.9 — II-295 — — A7.5 — II-296 — — A 8.9 — II-298 353.4 — B 2.8 — II-299 421.3 423.2 A10.1 —

Example 6

[0127] ERK Inhibition Assay:

[0128] Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%)for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP. The rate ofdecrease of absorbance at 340 nM was monitored. The IC₅₀ was evaluatedfrom the rate data as a function of inhibitor concentration.

[0129] Table 4 shows the results of the activity of selected compoundsof this invention in the ERK2 inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having anactivity designated as “A” provided a K_(i) value below 1 micromolar;compounds having an activity designated as “B” provided a K_(i) valuebetween 1 and 5 micromolar; and compounds having an activity designatedas “C” provided a K_(i) value greater than 5 micromolar. TABLE 4 ERK2Inhibitory Activity of Selected Compounds No. Activity No. Activity No.Activity II-1 A II-2 C II-3 A II-4 A II-5 A II-6 A II-7 C II-8 C II-9 CII-10 C II-11 C II-12 C II-13 A II-14 C II-16 C II-17 C II-18 A II-19 AII-20 A II-21 C II-22 A II-23 A II-24 A II-25 C II-26 A II-27 A II-28 AII-29 C II-30 A II-31 C II-39 A II-40 A II-41 A II-42 A II-43 A II-44 AII-45 A II-46 A II-47 A II-48 A II-49 A II-50 A II-51 A II-52 A II-53 AII-54 A II-55 A II-56 A II-57 A II-58 A II-59 A II-60 A II-61 A II-62 AII-63 A II-64 A II-65 A II-66 A II-67 A II-68 A II-69 A II-70 A II-71 AII-72 A II-73 A II-74 A II-75 A II-76 A II-77 A II-78 A II-79 A II-80 AII-81 A II-82 A II-83 A II-84 A II-85 A II-86 A II-87 A II-88 A II-89 AII-90 A II-91 A II-92 A II-93 A II-94 A II-95 A II-96 A II-97 A II-98 AII-99 A II-100 A II-101 A II-102 A II-103 A II-104 A II-105 A II-106 AII-107 A II-108 A II-109 A II-110 A II-111 A II-112 A II-113 A II-114 AII-115 A II-116 B II-117 B II-118 B II-119 B II-120 B II-121 B II-122 BII-123 B II-124 B II-125 B II-126 B II-127 B II-128 B II-129 B II-130 BII-131 B II-132 B II-133 B II-134 B II-135 B II-136 B II-137 B II-138 BII-139 B II-140 B II-141 B II-142 B II-143 B II-144 B II-145 B II-146 BII-147 B II-148 B II-149 B II-150 B II-151 B II-152 B II-153 B II-154 BII-155 B II-156 B II-157 B II-158 B II-159 B II-160 B II-161 C II-162 CII-163 C II-164 C II-165 C II-166 C II-167 C II-168 C II-169 C II-170 CII-171 C II-172 C II-285 B II-286 C II-287 C II-288 B II-289 C II-290 BII-291 C II-292 C II-293 C II-294 C II-295 C II-296 C II-297 C II-298 CII-299 C

Example 7

[0130] ERK Inhibition Cell Proliferation Assay:

[0131] Compounds were assayed for the inhibition of ERK2 by a cellproliferation assay. In this assay, a complete media was prepared byadding 10% fetal bovine serum and penicillin/streptomycin solution toRPMI 1640 medium (JRH Biosciences). Colon cancer cells (HT-29 cell line)were added to each of 84 wells of a 96 well plate at a seeding densityof 10,000 cells/well/150 μL. The cells were allowed to attach to theplate by incubating at 37° C. for 2 hours. A solution of test compoundwas prepared in complete media by serial dilution to obtain thefollowing concentrations: 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, and0.08 μM. The test compound solution (50 μL) was added to each of 72cell-containing wells. To the 12 remaining cell-containing wells, onlycomplete media (200 μL) was added to form a control group in order tomeasure maximal proliferation. To the remaining 12 empty wells, completemedia was added to form a vehicle control group in order to measurebackground. The plates were incubated at 37° C. for 3 days. A stocksolution of ³H-thymidine (1 mCi/mL, New England Nuclear, Boston, Mass.)was diluted to 20 μCi/mL in RPMI medium then 20 μL of this solution wasadded to each well. The plates were further incubated at 37° C. for 8hours then harvested and analyzed for ³H-thymidine uptake using a liquidscintillation counter.

[0132] Selected compounds of this invention'that inhibit ERK in thecolon cell proliferation assay, with an IC₅₀ of less than 10 μM include:II-43, II-48, and II-45.

Example 8

[0133] JAK Inhibition Assay:

[0134] Compound inhibition of JAK may be assayed by the method describedby G. R. Brown, et al, Bioorg. Med. Chem. Lett. 2000, vol. 10, pp575-579 in the following manner. Into Maxisorb plates, previously coatedat 4° C. with Poly (Glu, Ala, Tyr) 6:3:1 then washed with phosphatebuffered saline 0.05% and Tween (PBST), is added 2 μM ATP, 5 mM MgCl₂,and a solution of compound in DMSO. The reaction is started with JAKenzyme and the plates incubated for 60 minutes at 30° C. The plates arethen washed with PBST, 100 μL HRP-Conjugated 4G10 antibody is added, andthe plate incubated for 90 minutes at 30° C. The plate is again washedwith PBST, 100 μL TMB solution is added, then the plates are incubatedfor another 30 minutes at 30° C. Sulfuric acid (100 μL of 1M) is addedto stop the reaction and the plate is read at 450 nM to obtain theoptical densities for analysis to determine IC₅₀ values.

Example 9

[0135] JNK Inhibition Assay:

[0136] Compounds were screened in the following manner for their abilityto inhibit JNK using a spectrophotometric coupled-enzyme assay. To anassay stock buffer solution containing 0.1 M HEPES buffer (pH 7.5), 10mM MgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM EGF receptor peptide(with sequence KRELVEPLTPSGEAPNQALLR), were added various concentrationsof the compound in DMSO and a fixed concentration (10 nM) of activatedJNK. The resulting mixture was incubated at 30° C. for 10 minutes thenthe reaction was initiated by the addition of 10 μM ATP. The decrease ofabsorbance at 340 nM at 30° C. was monitored as a function of time andthe resulting data was fitted to a competitive inhibition kinetic modelto determine the K_(i).

[0137] Table 5 shows the results of the activity of selected compoundsof this invention in the JNK inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having anactivity designated as “A” provided a K_(i) value below 1 micromolar;compounds having an activity designated as “B” provided a K_(i) valuebetween 1 and 5 micromolar; and compounds having an activity designatedas “C” provided a K_(i) value greater than 5 micromolar. TABLE 5 JNKInhibitory Activity of Selected Compounds No. Activity No. ActivityII-39 B II-48  A II-40 A II-51  B II-43 A II-55  A II-46 A II-104 BII-47 B II-112 C

Example 10

[0138] Aurora Inhibition Assay:

[0139] Compounds were screened in the following manner for their abilityto inhibit Aurora using a standard coupled enzyme assay. To an assaystock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl₂, 25 mMNaCl, 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/mL pyruvate kinase,10 μg/mL lactate dehydrogenase, 40 μM ATP, and 800 μM peptide (LRRASLG,American Peptide, Sunnyvale, Calif.) was added a 30 μM solution of thecompound in DMSO and the resulting mixture incubated at 30° C. for 10min. The reaction was initiated by the addition of 10 μL of 70 μM Auroraand 1 mM DTT. The rates of reaction were obtained by monitoringabsorbance at 340 nM over a 5 minute read time at 30° C. using a BioRadUltramark plate reader (Hercules, Calif.). The IC₅₀ was determined fromthe rate data as a function of inhibitor concentration.

[0140] Table 6 shows the results of the activity of selected compoundsof this invention in the Aurora2 inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having anactivity designated as “A” provided an IC₅₀ value below 5 micromolar;compounds having an activity designated as “B” provided an IC₅₀ valuebetween 5 and 10 micromolar; and compounds having an activity designatedas “C” provided an IC₅₀ value greater than 10 micromolar. TABLE 6Aurora2 Inhibitory Activity of Selected Compounds No. Activity No.Activity No. Activity II-48 A II-89 A II-211 B II-51 B II-93 A II-212 BII-54 B II-98 B II-213 B II-57 A II-99 A II-214 B II-61 A II-101 AII-215 B II-64 A II-103 B II-216 B II-66 B II-106 B II-218 B II-70 BII-108 B II-228 A II-72 B II-112 A II-252 B II-76 A II-113 A II-254 AII-77 A II-114 A II-255 B II-80 C II-115 A II-258 C II-81 A II-141 AII-259 B II-82 A II-142 A II-260 C II-85 B II-181 B II-262 B II-88 BII-188 C II-266 B

Example 11

[0141] GSK-3 Inhibition Assay:

[0142] Compounds were screened in the following manner for their abilityto inhibit Glycogen Synthase Kinase 3 (GSK-3) using a standard coupledenzyme assay (Fox et al (1998) Protein Sci 7, 2249). To an assay stockbuffer solution containing 0.1M HEPES 7.5, 10 μM MgCl₂, 25 mM NaCl, 2.5mM phosphoenolpyruvate, 300 μM NADH, 1 mM DTT, 30 μg/mL pyruvate kinase,10 μg/mL lactate dehydrogenase, 300 μM peptide (HSSPHQp-SEDEEE, AmericanPeptide, Sunnyvale, Calif.), and 60 nM GSK-3, was added a 30 μM solutionof the compound in DMSO and the resulting mixture incubated at 30° C.for 5 min. The reaction was initiated by the addition of 10 μM ATP. Therates of reaction were obtained by monitoring absorbance at 340 nM overa 5 minute read time at 30° C. using a Molecular Devices plate reader(Sunnyvale, Calif.). The IC₅₀ was determined from the rate data as afunction of inhibitor concentration.

[0143] Table 7 shows the results of the activity of selected compoundsof this invention in the GSK-3 inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having anactivity designated as “A” provided an IC₅₀ value below 10 micromolar;compounds having an activity designated as “B” provided an IC₅₀ valuebetween 10 and 20 micromolar; and compounds having an activitydesignated as “C” provided an IC₅₀ value greater than 20 micromolar.TABLE 7 GSK-3 Inhibitory Activity of Selected Compounds No. Activity No.Activity No. Activity II-89 C II-115 C II-263 A II-93 C II-127 B II-271A II-94 C II-199 C II-278 A II-99 A II-214 C — — II-108 B II-227 B — —

Example 12

[0144] KDR Inhibition Assay:

[0145] Compounds were screened for their ability to inhibit KDR using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 200 mM HEPES 7.5, 10 mMMgCl2, 25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 300 μM ATP (Sigma Chemicals) and 10 μM.poly E4Y (Sigma). Assays were carried out at 37° C. and 30 nM KDR. Finalconcentrations of the components of the coupled enzyme system were 2.5mM phosphoenolpyruvate, 200 μM NADH, 30 μg/ML pyruvate kinase and 10μg/ml lactate dehydrogenase.

[0146] An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 177 pl of the stock solution was placed in a 96 well platefollowed by addition of 3 ul of 2 mM DMSO stock containing the testcompound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 37° C. and the reaction initiatedby addition of 20 μl of ATP (final concentration 300 μM). Rates ofreaction were obtained using a Molecular Devices plate reader(Sunnyvale, Calif.) over a 5 minute read time at 37° C. Compoundsshowing greater than 50% inhibition versus standard wells containing theassay mixture and DMSO without test compound were titrated to determineIC₅₀ values.

[0147] Selected compounds of this invention that inhibit KDR at 2 μMconcentration in the above assay, with a percent inhibition of greaterthan 40%, include: II-43, II-48, II-304, and II-305.

Example 13

[0148] AKT Inhibition Assay:

[0149] Compounds were screened for their ability to inhibit AKT using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7.,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl₂, 25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 μMpeptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays werecarried out at 30° C. and 45 nM AKT. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactatedehydrogenase.

[0150] An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showinggreater than 50% inhibition versus standard wells containing the assaymixture and DMSO without test compound were titrated to determine IC₅₀values.

[0151] Selected compounds of this invention that inhibit AKT include:II-89, II-94, and II-305.

[0152] While we have described a number of embodiments of thisinvention, it is apparent that our basic examples may be altered toprovide other embodiments which utilize the compounds and methods ofthis invention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments which have been represented by way of example.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: R¹ is selected from R, halogen, N(R⁸)₂, OR, NRCOR, NRCON(R⁸)₂, CON(R⁸)₂, SO₂R, NRSO₂R, or SO₂N(R⁸)₂; T is selected from a valence bond or a linker group; each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons; R² is selected from hydrogen, CN, halogen, aryl, aralkyl, heteroaryl, heterocyclyl, an optionally substituted acyclic aliphatic chain group having one to six carbons, or an optionally substituted cyclic aliphatic group having four to ten carbons; R³ is selected from R, OH, OR, N(R⁸)₂, halogen, or CN; Q is a valence bond, J, or an optionally substituted C₁₋₆ alkylidene chain wherein up to two nonadjacent carbons of the alkylidene chain are each optionally and independently replaced by J; J is selected from —C(═O)—, —CO₂—, —C(O)C(O)—, —NRCONR⁸—, —N(R)N(R⁸)—, —C(═O)NR⁸—, —NRC(═O)—, —O—, —S—, —SO—, —SO₂—, —N(R)O—, —ON(R⁸)—, —OC(═O)N(R⁸)—, —N(R)COO—, —SO₂N(R⁸)—, —N(R)SO₂—, or —N(R⁸)—; R⁴ is selected from —R⁸, —R⁵, —NH₂, —NHR⁵, —N(R⁵)₂, or —NR⁵(CH₂)_(y)N(R⁵)₂; each R⁵ is independently selected from R⁶, R⁷, —(CH₂)_(y)CH(R⁶)(R⁷), —(CH₂)_(y)R⁶, —(CH₂)_(y)CH(R⁶)₂, —(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷; y is 0-6; each R⁶ is an optionally substituted group independently selected from an aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxy, group; each R⁷ is independently selected from an optionally substituted aliphatic, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; and each R⁸ is independently selected from R, or two R⁸ on the same nitrogen taken together with the nitrogen optionally form a four to eight membered, saturated or unsaturated heterocyclic ring having one to three heteroatoms; provided that QR⁴ is other than CON(CH₃)₂ when R¹ and R³ are each hydrogen and when TR² is an unsubstituted phenyl ring attached at the 4-position of the pyrazole ring.
 2. The compound according to claim 1 having the formula

or a pharmaceutically acceptable derivative or prodrug thereof.
 3. The compound according to claim 2 having one or more of the following features: (a) Q is —CO—, —CO₂—, or —CONH—; (b) T is a valence bond; (c) R¹ is hydrogen or NHR; (d) R² is an optionally substituted aryl ring; (c) R³ is hydrogen; (e) R⁴ is selected from R⁵, —NHR⁵, —N(R⁵)₂, —NR⁵R⁶, —NHCHR⁵R⁶, or —NHCH₂R⁵; or (f) R⁵ is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group, (CH₂)_(y)R⁶, (CH₂)_(y)R⁷, or (CH₂)_(y)CH(R⁶)(R⁷).
 4. The compound according to claim 3 having the formula

or a pharmaceutically acceptable derivative or prodrug thereof.
 5. The compound according to claim 4 having the following features: (a) T is a valence bond; (b) R² is an optionally substituted aryl ring; (c) R⁴ is selected from R⁵, —NHR⁵, —N(R⁵)₂, —NR⁵R⁶, —NHCHR⁵R⁶, or —NHCH₂R⁵; and (d) R⁵ is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group, (CH₂)_(y)R⁶, (CH₂)_(y)R⁷, or (CH₂)_(y)CH(R⁶)(R⁷).
 6. The compound according to claim 1 wherein said compound is selected from those listed in Table 1, said compound being other than compound number
 1. 7. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable derivative or prodrug thereof.
 8. The compound according to claim 7 wherein said compound has one or more of the following features: (a) T is a valence bond; (b) R² is an optionally substituted aryl ring; (c) R⁴ is selected from R⁵, —NHR⁵, —N(R⁵)₂, —NR⁵R⁶, —NHCHR⁵R⁶, or —NHCH₂R⁵; or (d) R⁵ is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group, (CH₂)_(y)R⁶, (CH₂)_(y)R⁷, or (CH₂)_(y)CH(R⁶)(R⁷).
 9. The compound according to claim 1 wherein said compound is selected from those listed in Table
 2. 10. A composition comprising a compound according to any one of claims 1 to 9 in an amount sufficient to detectably inhibit protein kinase activity, said protein kinase selected from one or more of ERK, JAK, JNK, Aurora, GSK, KDR, AKT, or a protein kinase related thereto; and a pharmaceutically acceptable carrier.
 11. The composition according to claim 10 wherein said compound is formulated in a pharmaceutically acceptable manner for administration to a patient.
 12. A composition according to claim 11 further comprising a therapeutic agent, either as part of a multiple dosage form together with said compound or as a separate dosage form.
 13. A method of inhibiting protein kinase activity in a biological sample, wherein said protein kinase is selected from ERK, JAK, JNK, Aurora, GSK, KDR, AKT, or a protein kinase related thereto, comprising the step of contacting said sample with a compound according to any one of claims 1 to
 9. 14. A method for treating a protein kinase-mediated disease state in a patient, wherein said protein kinase is selected from one or more of ERK, JAK, JNK, Aurora, KDR, AKT, or a protein kinase related thereto, comprising the step of administering to said patient a composition according to claim
 11. 15. The method according to claim 14, comprising the additional step of administering to said patient a therapeutic agent either as part of a multiple dosage form together with said compound or as a separate dosage form.
 16. A method of treating a disease state in a patient, wherein said disease state is selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, or CNS disorders, comprising the step of administering to said patient a composition according to claim
 10. 17. The method according to claim 16 wherein the disease state is cancer.
 18. The method according to claim 17 wherein the disease state is a cancer selected from breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum, large intestine, rectum; brain and central nervous system; or leukemia.
 19. The method according to either of claims 17 or 18 comprising the additional step of administering to said patient a chemotherapeutic agent either as part of a multiple dosage form together with said compound or as a separate dosage form.
 20. The method according to claim 16 wherein the disease state is cardiovascular disease.
 21. The method according to claim 20 wherein the disease state is a cardiovascular disease selected from restenosis, cardiomegaly, artherosclerosis, myocardial infarction, or congestive heart failure.
 22. The method according to either of claims 20 or 21 comprising the additional step of administering to said patient a therapeutic agent for treating cardiovascular disease either as part of a multiple dosage form together with said compound or as a separate dosage form.
 23. A composition for coating an implantable device comprising a compound according to claim 1 and a carrier suitable for coating said implantable device.
 24. An implantable device coated with a composition according to claim
 23. 